HLA-A, B, DR, and DQ antigens in black patients with severe chronic rheumatic heart disease

To determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease, we performed HLA-A and HLA-B typing in 120 black patients with severe chronic rheumatic heart disease requiring cardiac surgery, and HLA-DR and HLA-DQ typing in 103 and 97 of these patients, respectively. The HLA typing was done by a standard microlymphocytotoxicity method. Patients were 12 to 60 years old (mean 27.6 +/- 14.5). No differences in HLA-A, HLA-B, and HLA-DQ frequencies between patients and controls were noted. HLA-DR 1 antigen was present in 12.6% of patients compared with 2.7% of normal control subjects (corrected p less than .045; relative risk = 5.2) and the HLA-DRw6 antigen was present in 31.1% of patients compared with 15% of control subjects (corrected p less than .045; relative risk = 2.6). These findings suggest that genetically determined immune-response factors may play a role in the pathogenesis of severe chronic rheumatic heart disease.     

Association of HLA-DR7 with rheumatic fever in the Brazilian population

OBJECTIVE: Rheumatic fever (RF) is a multisystem inflammatory disease that develops as a sequel of untreated throat infection by the group A beta-hemolytic streptococcus. As HLA antigens are known to be important in controlling immunological responsiveness, studies have investigated HLA antigen association with RF. Studies with Caucasians, Black Americans, and Indians showed associations with HLA-DR4, DR2, and DR3, respectively. One study on a Brazilian population suggested an association with HLA-DR7 and HLA-DR53. We investigated the association between RF and antigens HLA-DR7 and DR53 in the white Brazilian population. METHODS: Thirty-five patients and 209 healthy individuals living in the northern region of the state of Parana, Brazil, were used as test and control groups, respectively. Classical statistical methods were used to compare HLA frequencies between these groups. Results. Data confirmed positive association with HLA-DR7 (46.7 vs. 25.7%; p = 0.015), but not with HLA-DR53 (54.3 vs. 44.5%; p = 0.28). The relative risk and etiologic fractions were 2.4 and 0.27%, respectively. CONCLUSION: Positive association between HLA-DR7 specificity and RF was observed in the white Brazilian population by 2 independent studies, supporting the hypothesis of the involvement of genetic factors in susceptibility of rheumatic fever.     

A genetic marker for rheumatic heart disease

The frequency of antigen types (A, B, C, and DR) in an unselected group of 25 patients with chronic rheumatic heart disease and an unselected group of 15 patients with acute rheumatic fever was compared with that in a group of 100 healthy volunteers. All patients and controls were Arabs of Saudi origin. Only the frequency of HLA-DR4 was significantly different in the controls and the patient groups--controls 12%, chronic rheumatic heart disease 72%, acute rheumatic fever 53%, both patient groups together 65% (relative risk 13.6 with 95% confidence interval 10.5-16.7). Eighty three per cent of 12 patients with mitral stenosis and 70% of seven with aortic incompetence had HLA-DR4 antigen. In 17 non-Saudi Arab patients who had acute rheumatic fever or chronic rheumatic heart disease, the frequency of HLA-DR4 was identical (65%) to that in Saudi patients. These findings may have implications for the pathogenesis of rheumatic fever and rheumatic heart disease.     

A genetic marker for rheumatic heart disease.

The frequency of antigen types (A, B, C, and DR) in an unselected group of 25 patients with chronic rheumatic heart disease and an unselected group of 15 patients with acute rheumatic fever was compared with that in a group of 100 healthy volunteers. All patients and controls were Arabs of Saudi origin. Only the frequency of HLA-DR4 was significantly different in the controls and the patient groups--controls 12%, chronic rheumatic heart disease 72%, acute rheumatic fever 53%, both patient groups together 65% (relative risk 13.6 with 95% confidence interval 10.5-16.7). Eighty three per cent of 12 patients with mitral stenosis and 70% of seven with aortic incompetence had HLA-DR4 antigen. In 17 non-Saudi Arab patients who had acute rheumatic fever or chronic rheumatic heart disease, the frequency of HLA-DR4 was identical (65%) to that in Saudi patients. These findings may have implications for the pathogenesis of rheumatic fever and rheumatic heart disease.     

抗DNA酶B滴度测定在风湿性心脏病诊断中的价值

目的　探讨抗 DNA酶 B检测用于风湿性心脏病诊断的价值。方法　检测 43例风湿性心脏病伴活动性风湿热 ,39例风湿性心脏病不伴风湿热活动和 40例非风湿性心脏病 (对照组 )病人血清的抗 DNA酶 B抗体 ,并进行对比。结果　风湿性心脏病伴活动性风湿热组 ,风湿性心脏病不伴风湿热组和对照组抗 DNA酶 B阳性率分别为81.4% ,2 0 .1%和 5 % ,与对照组比较 ,前两组的 P值分别为 <0 .0 0 1和 <0 .0 5。结论　抗 DNA酶 B检测可以作为诊断风湿性心脏病伴活动性风湿热的一个指标     

风湿性心脏炎HLA—DR分子表达量的改变

目的　了解风湿性心脏炎 (rheumaticcarditis,RC)外周血淋巴细胞表面HLA DR分子的表达量 ,以探讨HLA DR分子在外周血淋巴细胞表面的表达量在RC发病机制中的意义 ,为RC的诊断和防治提供新的途径。方法　选取门诊及住院确诊风湿性心脏炎者 33例 ,单纯风湿性关节炎 2 1例 ,风心病静止期组 36例 ,链球菌感染后状态组 16例 ,正常对照组 43例。分别予A组 β型溶血性链球菌 (GAS)膜抗原及GM CSF刺激其淋巴细胞 ,另设空白对照 ,参照RandallEllisMorris的cell ELISA方法 ,检测淋巴细胞表面HLA DR的表达情况 ,以OD/cell为单位表示。HLA DR表达量以均数±标数差表示 ,用方差分析其差异 ,P <0 0 5为统计学显著标准。结果　①心脏炎组HLA DR分子表达量明显高于其他各组 (P <0 0 5 ) ,而关节炎组较非活动期组亦有明显增高 (P<0 0 5 )。②加入膜抗原及GM CSF后各样本的HLA DR的表达量均有增加。加入膜抗原刺激者 ,心脏炎组的增加量较其他各组明显大 ,而关节炎组和风心病静止期组增加量与正常对照组及链球菌感染后状态组相比亦有显著差别 (P <0 0 5 )。结论　①对HLA DR分子表达量的检测有助于对风湿热不同型别及不同病期的诊断和监测风湿性心脏炎的活动情况。②膜抗原与HLA DR分子对风湿性心脏炎发病及发展起了重要     

A community-based rheumatic fever/rheumatic heart disease cohort: twelve-year experience

BACKGROUND: A pilot rheumatic fever and rheumatic heart disease control porject was started in 1988 in blocks of district Ambala (Haryana) to test the feasibility of early detection, treatment and secondary prophylaxis for rheumatic fever/rheumatic heart disease cases. School teachers, students and health workers were trained to identify and refer suspected cases of rheumatic fever/rheumatic heart disease to the community health center where physicians examined the suspected cases and monthly secondary prophylaxis was provided to the confirmed cases. METHODS AND RESULTS: A survey of registered cases was done in 1999 to determine the compliance rate of secondary prophylaxis and to describe clinical and epidemiologic features of the registered cohort of rheumatic fever/rheumatic heart disease patients. A total of 257 patients had been registered till the end of 1999 with 1263 person-years of follow-up. Out of these registered patients, 132 were receiving secondary prophylaxis, 52 had died, 17 had migrated, 8 were lost to follow-up, 18 had stopped prophylaxis and 30 completed the prophylaxis course. The mean age at registration was 18 years. Half of the cases were in the 6-15 years age group at registration. Over half of the patients were registered with a history of rheumatic fever. Fever was the most common symptom (75.9%). Carditis was more common among cases with recurrent attacks of rheumatic fever than after a first attack. The mortality in rheumatic fever/rheumatic heart cases was 32.5/1000 person-years. The mean age at death was 24.4 years. Compliance with secondary prophylaxis was 92% during the past 12 years. CONCLUSIONS: A rheumatic fever/rheumatic heart disease control program can be sustained within the primary health care system and the case registry can be utilized not only for monitoring the program but also to gain insight into the epidemiology of the disease.     

HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies.

We previously reported antigen frequency differences for HLA-DR4 and HLA-DRw6 between idiopathic dilated cardiomyopathy (IDC) patients and healthy controls in a pilot study. To confirm these findings, we undertook an independent study with a prospective hypothesis regarding the frequencies of DR4 and DRw6; typing for a second family of class II antigens (HLA-DQ) was included because of the proximity of the DQ loci to the DR loci and the strong linkage disequilibrium between some of the DR and DQ alleles. Comparing a new consecutive series of IDC patients (n = 41) and healthy blood bank controls (n = 53), we confirmed an increase of DR4 antigen frequency in patients (49% versus 21%, p less than 0.005). A trend toward decreased expression of DRw6 among patients was also noted (10% of patients versus 23% of controls). HLA-DQw4 was significantly elevated in patients compared with controls (27% versus 6%, p less than 0.005; relative risk, 6.1; etiologic fraction, 0.22). We identified the combined DR4-DQw4 haplotype in five of 41 Caucasian IDC patients (12%) and none of 53 controls (p less than 0.007). A comparison of specific antigen frequencies between the preliminary and validation studies did not reveal significant differences; therefore, the data from the two studies were examined in combination. For the combined studies, DR4 was elevated (51% versus 27% in controls, p less than 0.001), and DRw6 was decreased (9% versus 24% in controls, p less than 0.01). The relative risk for DR4 was 2.8, and the etiologic fraction was 0.33.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lymphocyte subsets in acute rheumatic fever and rheumatic heart disease

Lymphocyte subsets in 53 patients with acute rheumatic fever and 78 patients with chronic rheumatic heart disease were compared with 20 normal control subjects and 39 patients suffering from uncomplicated streptococcal pharyngitis to obtain information about the pathogenesis of the disease. Twenty patients with rheumatic fever were followed for 24 weeks to evaluate changes occurring over the course of the disease. Total leukocyte and lymphocyte counts were increased in patients with rheumatic fever and to a lesser extent in those with rheumatic heart disease, when compared with controls. The difference between the two groups was significant. Patients with acute rheumatic fever had an increased number of B cells and a smaller increase in total T and T-helper-inducer (CD-4) cells. The proportion of B cells increased, while that of T-suppressor-cytotoxic (CD-8) cells fell. An increased number and proportion of B cells was also seen in patients with rheumatic heart disease. Total T and T-helper lymphocyte percentages and numbers were significantly higher in patients with rheumatic fever compared with those of patients with rheumatic heart disease. Follow-up studies at 6, 12, and 24 weeks revealed no significant differences from the entry point studies, although there was a trend toward reduction in the degree of derangement from normal values. Patients with uncomplicated streptococcal pharyngitis, however, did not show perturbations in the T-cell and T-subset counts. Our study suggests that the immunoregulatory defect in acute rheumatic fever is characterized by a relative reduction of suppressor T cells with an absolute increase in helper T cells and B cells, resulting in an increased cellular as well as humoral immune response.(ABSTRACT TRUNCATED AT 250 WORDS)     

The HLA complex and its relationship to rheumatic diseases

The HLA complex has been shown to be involved in the regulation of several aspects of the immune response, and has been shown to be associated with several rheumatologic diseases. The mechanisms by which HLA molecules predispose to disease has been an area of intense interest. Recent work has provided some possible explanations for the lack of absolute associations between a particular disease and a particular HLA antigen. There is now some evidence to suggest that specific epitopes rather than entire class I or II molecules may be responsible for disease predisposition. Furthermore, it appears that these epitopes may be transferred between different class I and II molecules by a mechanism known as gene conversion. Work evaluating the influence of other genes, such as those for the T cell receptor, on disease susceptibility has just begun. Many of the rheumatic diseases are quite diverse in their presentation. If only one of a heterogeneous group of diseases is associated with an HLA antigen, study of the entire group of diseases will of necessity dilute the association. Better definitions of clinical subsets should lead to improved correlations of HLA and disease. Little is known of etiologic agents or pathogenesis. As our knowledge of the interaction of HLA antigens, T cell receptors, and etiologic agents increases, we will come closer to an understanding of the mechanisms by which these molecules predispose to disease.     

HL-A antigens in Europeans and Maoris with rheumatic fever and rheumatic heart disease.

Using a standard microtoxicity technique of tissue typing, the distribution of tissue antigens in 75 Maoris and 514 European disease-free blood donors was determined. Fifty Maori and 50 Europeans with rheumatic fever or rheumatic heart disease were compared with each control group. Normal Maoris had HL-A3 less frequently than Europeans (P less than .0005). HL-A28 was reduced (P less than .005) and HL-A17 increased in European patients (P less than .0005). In Maori patients there were minor differences in the frequency of HL-A3 and 8, which were increased, and HL-A10, which was diminished.     

Hashimoto's thyroiditis and HLA in Japanese

To investigate genetic factors involved in the pathogenesis of Hashimoto's thyroiditis (HT; goitrous autoimmune thyroiditis), HLA class I and class II antigens were analyzed in both seropositive HT (99 patients) and seronegative HT (43 patients). The frequency of HLA-DRw53 antigen was increased significantly in both seropositive HT (antigen frequency, 0.83; relative risk, 33.3; P less than 0.0002; corrected P less than 0.001) and seronegative HT (antigen frequency, 0.81; relative risk, 3.02; P less than 0.01; corrected P less than 0.05). The etiological fraction values for HLA-DRw53 in seropositive HT and seronegative HT were 0.58 and 0.54, respectively. An increased frequency of HLA-DQw4 and a decreased frequency of HLA-DQw1 were observed in patients with seronegative HT. These data suggest that susceptibility to HT is primarily associated with HLA-DRw53 and that HLA-DQ alleles may control the production of autoantibodies to the thyroid gland. The mode of inheritance of disease susceptibility for HT (controlled by a major gene in linkage disequilibrium with HLA-DRw53) was investigated by the method of Thomson and Bodmer, and it was suggested that disease susceptibility was inherited in a dominant manner.     

Immunogenetic study of the response to streptococcal carbohydrate antigen of the cell wall in rheumatic fever.

An immunogenetic study of the response to streptococcal carbohydrate antigen of the cell wall was carried out on members of 15 multiplex families each having more than one sib affected with rheumatic heart disease. They comprised 30 parents and 61 sibs (32 with rheumatic disease and 29 without). Fifty healthy unrelated subjects served as controls. A history was taken and clinical examination carried out. Rheumatic activity was determined and HLA typing was carried out for nine A antigens, 15 B antigens, and six DR antigens. The immune response of lymphocytes to streptococcal polysaccharide antigen of the cell wall of group A beta haemolytic streptococci in vitro was studied by tritiated thymidine uptake. The results were statistically and genetically analysed. It was found that (a) all subjects with rheumatic disease were highly responsive to the streptococcal polysaccharide antigen of the cell wall, the sib pairs being mostly HLA identical; (b) all low responders had no rheumatic disease and their phenotypes were mostly different from those of the rheumatic member of their sib pair; (c) correlation of immune responsiveness (high or low) between HLA-identical sibs was significant, but insignificant between haplotype identical and non-identical sibs; (d) the gene responsible for high responsiveness to the streptococcal polysaccharide antigen of the cell wall is recessive and closely linked to HLA. In conclusion, it was found that exposure to pharyngeal infection with group A beta haemolytic streptococci may lead to acute rheumatic fever in those with an inherited recessive gene responsible for high responsiveness to the streptococcal polysaccharide antigen of the cell wall.     

Antibody titer to group A streptococcal polysaccharide in rheumatic fever and rheumatic heart disease

Antibody to group A streptococcal polysaccharide (ASP) is the only antibody of cellular components which is now detectable in clinical practice. Streptococcal polysaccharide is known to have cross-immunity with the glycoprotein of human heart tissue, and has been discussed as a pathogenesis of rheumatic carditis and valvular heart disease. In this study, ASP titer was determined by passive hemagglutination technique in patients with rheumatic fever and rheumatic heart disease. ASP titer showed higher levels in these patients compared to control children, but there was no specificity in rheumatic carditis or rheumatic heart disease.     

Midterm outcomes of rheumatic mitral repair versus replacement

Mitral repair is feasible for patients with degenerative or ischemic heart disease, however, the appropriateness of repair for rheumatic heart disease remains controversial. We compared our outcomes for primary isolated mitral repair versus replacement in an elderly population. From November 1997 to July 2005, mitral repair (group I) was performed in 33 patients while 59 underwent replacement (group II). Survival and risk factors were evaluated by Kaplan-Meier and Cox regression analysis. Mean age at operation for groups I and II was 49.7 +/- 13.2 versus 58.1 +/- 11.2 (P = 0.002). No statistically significant differences with regards to demographic parameters were observed except for there being fewer percutaneous transvenous mitral commissurotomy procedures and a lower severity of pulmonary hypertension in group I. Patients with a greater Wilkins score and more valvular calcification underwent replacement more often (P < 0.001). In-hospital mortality, ICU/hospital stay, and postoperative congestive heart failure functional class did not differ significantly. Major adverse cardiac events occurred in 13 and 19 patients, respectively (P = 0.50). There were 4 versus 6 late deaths (P = 0.74). Only two from group I underwent subsequent mitral reoperation. Kaplan-Meier overall survival and event-free survival at 5 years for groups I and II were 0.81 +/- 0.08 versus 0.81 +/- 0.06 (P = 0.90) and 0.52 +/- 0.10 versus 0.51 +/- 0.10 (P = 0.21), respectively. Old age, renal insufficiency, LVEF < 40%, and a history of stroke were poor predictors of patient survival. Compared with replacement, mitral repair for rheumatic heart disease was associated with a lower surgical mortality, higher repeat-surgery rate, and good survival. Rheumatic mitral valves should be repaired in select patients with appropriate valvular pathology.     

HLA-DR typing and lymphocyte subset evaluation in rheumatic heart disease: a search for immune response factors

Several autoimmune diseases have been associated with increased frequencies of specific histocompatibility (HLA) antigens, particularly for the D (DR) locus, that may be linked to immune response genes. Rheumatic valvular heart disease (RHD) has been postulated to have autoimmune features, but HLA associations have not been established. We, therefore, performed HLA-DR typing in 33 consecutive patients with RHD and in 82 normal blood bank control subjects. We also evaluated the frequencies of lymphocyte subsets by means of monoclonal antibodies and immunofluorescence flow cytometry and made functional correlations for the natural killer cell (NKC) in patient subsets. The DR patterns in RHD were heterogeneous. However, significant differences were noted for DR4 and DR6. DR4 was present in 52% (17 of 33) of RHD patients vs 32% (26 of 82) of control subjects (p less than 0.05). DR6 was present in 6% (2 of 33) of patients vs 26% (21 of 82) of control subjects (p less than 0.02). The associated relative odds of DR4 was 2.3 and the etiologic fraction was 0.30. The relative odds of DR6 was 0.19 and the preventive fraction was 0.21. A distinct clinical profile was not associated with DR4 positivity or DR6 negativity. The frequency of lymphocyte subsets was not significantly changed except for OKT8. Median NKC numbers tended to be higher in RHD patients than in control subjects (p less than 0.05). In contrast, NKC functional activity tended to be lower in RHD; median lymphocyte to target cell (K562 line) ratio resulting in 50% killing (L/T 50) was 20.5 in RHD patients vs 11.5 in control subjects (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA histocompatibility antigens in patients with aortic valve defects

HLA antigens A, B, C were determined in 61 patients with aortic valve disease and in 263 healthy controls. The patients were divided into two subgroups--with rheumatic fever in anamnesis (N = 24) and without (N = 37). In the whole group of patients with aortic valve disease there was a lower frequency of incidence of HLA A3 in comparison to the control group. In the subgroup with rheumatic fever in anamnesis there was a deficit of HLA A3 and a much more frequent incidence of HLA B17, in the subgroup without rheumatic fever a more frequent incidence of HLA A2, A9, A28, B15 was noted in comparison to the control group. This study shows that in 60% of patients with aortic valve disease the etiology is linked not to rheumatic fever but probably to a connective tissue disorder. A deficit of HLA A3 and presence of B17 can be a risk factor for rheumatic fever.     

Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients

Serum samples from patients with connective tissue disease (CTD) were characterized using a recently developed enzyme-linked immunosorbent assay for reactivity with individual specific polypeptides of U1 small nuclear ribonucleoproteins, including the U1-70-kd protein. The distribution of HLA antigens was compared in CTD patients with and in those without anti-U1-70-kd autoantibodies and in normal controls. The frequencies of HLA-DR4 and HLA-DRw53 were increased among the anti-U1-70-kd autoantibody positive CTD group compared with the frequencies in anti-U1-70-kd autoantibody negative systemic lupus erythematosus patients and compared with normal controls. We conclude that the presence of autoantibodies reactive with the anti-U1-70-kd protein antigen is associated with HLA-DR4 and HLA-DRw53.     

HLA association with dermatitis herpetiformis is accounted for by a cis or transassociated DQ heterodimer.

HLA-DR, DQ, and DP restriction fragment genotyping was undertaken in 23 dermatitis herpetiformis patients and 53 healthy control subjects. HLA-DQw2 was present in 100% of patients with dermatitis herpetiformis (23 of 23) versus 40% of control subjects (21 of 53). Significant secondary associations occurred with HLA-DR3 (91% of patients versus 28% of control subjects) and DPw1 (39% of patients versus 11% of control subjects). Dermatitis herpetiformis and coeliac disease thus share an identical HLA class II association. It is likely that HLA class II genes directly influence the immune responses leading to mucosal damage in both diseases. The strongest candidate for disease susceptibility to dermatitis herpetiformis is DQw2. The HLA molecule most likely to be involved in coeliac disease is a specific DQ alpha/DQ beta heterodimer, encoded in cis arrangement in DR3 haplotypes or in trans arrangement in a DR5, 7 genotype. Our data on dermatitis herpetiformis patients fits this model perfectly. All these patients are capable of expressing this molecule, which may be responsible for the gluten sensitive enteropathy seen in a subgroup of patients with dermatitis herpetiformis and coeliac disease.     

Understanding rheumatic fever

Through a comprehensive review of the recent findings on rheumatic fever, we intend to propose a new physiopathologic model for this disease. A Medline search was performed for all articles containing the terms rheumatic fever or rheumatic heart disease in title or abstract from 1970 to 2011. Best evidence qualitative technique was used to select the most relevant. The scientific interest on rheumatic fever has notably diminished throughout the twentieth century as evidenced by the comparison of the proportion of articles in which RF was a subject in 1950 (0.26%) and today (0.03%) [Pubmed]. However, RF remains a major medical and social problem in the developing world and in the so-called hotspots, where it still causes around 500.000 deaths each year, not too different from the pre-antibiotic era. The role of genetic factors in RF susceptibility is discussed. Familiar aggregation, similarity of disease patterns between siblings, identical twin, and HLA correlation studies are evidence for a genetic influence on RF susceptibility. The suspect-involved genes fall mainly into those capable of immunologic mediation. Molecular mimicry explains the triggering of RF, but an intense and sustained inflammation is needed to cause sequels. Also, RF patients vary greatly in terms of symptoms. It is likely that a genetic background directing immune response towards a predominantly Th1 or Th2 pattern contributes to these features. The recent findings on rheumatic fever provide important insight on its physiopathology that helps understanding this prototype post-infectious autoimmune disease giving insights on other autoimmune conditions.